1. INTRODUCTION:

Benzo-fused azoles, such as benzimidazoles, benzoxazole and azoles containing 3 hetero atoms have received immense consideration for their significant medicinal properties [1-15]. Amongst these, N-substituted benzotriazoles are the most important derivatives of benzotriazoles which are used for the synthesis of various bio-active compounds having activities such as antifungal [16], antibacterial [16,17], anthelmintic [18], antihistaminic [19], DNA cleavage [20], antitubercular [21], anticancer [22], antiulcer [23], anti-nociceptive [24], anti-inflammatory [24], anticonvulsant [25], analgesic [25], protein kinase inhibitors [26], and respiratory syndrome protease inactivators, antiviral [27], etc.

The 1H-benzo[d][1,2,3]triazole (Fig. 1) is a significant chemical entity and can be used as scaffold or synthetic auxiliary for the design of novel therapeutically active compounds [28-32]. It can also be used as a good leaving group after reaction with a variety of carbonyl groups, an electron donor and a precursor of radicals or carbanions [33-36].

Fig. 1: Benzotriazole

It can be easily inserted into other chemical structures through a series of reaction, such as condensation, addition reactions and benzotriazolyl-alkylation [37-39]. Some authors have also reported the synthesis of stable nitrenium ions using benzotriazole as synthon [40]. By virtue of its important characteristics like the optimum solubility along with stability in acidic/ basic medium and in variety of solvents, easily implementation of standard reaction conditions during synthesis, activation during biotransformation and elimination, this moiety has proved a versatile molecule for synthetic, pharmacological and of other interest [41-47]. However, the main interest on benzotriazole is because of its value in the pharmaceutical field, as suitably substituted benzotriazole derivatives possess various medicinal activities against various lethal diseases caused by pathogenic microorganisms [48].

Despite the investments in antimicrobial drug discovery, no new drug class has been found in the past 20 years [49]. Additionally, due to increased antibiotics resistance, there is an urgency to develop new antimicrobial drugs [50]. For decades, Separator and co-workers analyzed and reported various nitrogen rings and concluded that benzotriazole possesses antibacterial activity [51-53]. Therefore, this class of compound have been investigated to have antimicrobial action in late 1980’s against microbes [54].

In addition to reported antibacterial activity of benzotriazoles, Schiff’s bases synthesized from aromatic amines/ aldehydes have also been reported to possess antimicrobial, anti-inflammatory, antifungal, antitumor and anticonvulsant activities [55, 56].

Therefore, it was predicted that compounds containing both benzotriazole and Schiff base would result in molecules having good antibacterial activity. A large number of Schiff bases of benzotriazolyl-4-amino-1,2,4-triazoles as shown in Fig. 2 and Table1 were synthesized and assessed by Prasad et al. for antifungal activity using cup plate agar diffusion method against Candida albicans, and compound (4) was found to be the most potent antifungal effect [57].

On the basis of reported potential of Schiff base as antimicrobial agents, we have focus on synthesis of derivatives of Schiff bases of benzotriazole by microwave technique[58, 59]] and evaluation of these synthesized derivatives for in vitro antibacterial activity.

Fig. 2: Schiff bases of benzotriazolyl-4-amino-1,2,4-triazoles

Table 1: List of Derivatives

S. No	R	S. No	R
1.	-H	8.	2-NO₂
2.	2-Br	9.	3-NO₂
3.	3-Br	10.	4-NO₂
4.	4-Br	11.	2-OCH₃
5.	2-Cl	12.	3-OCH₃
6.	3-Cl	13.	3-OCH₃
7.	4-Cl	14.	-N(CH₃)₂

2. MATERIAL AND METHODS:

The chemical used in our experimental work were procured from Electron LLS India Pvt. Ltd., Mumbai, Loba Chemie Pvt. Ltd., Mumbai, India, Changshu Yangyan Chemical., China, Thermo Electron LLS India Pvt. Ltd. Mumbai and Qualikems Fine Chem Pvt. Ltd. Vadodara, India.

The melting point was determined using open capillary method and were uncorrected. FTIR spectra were recorded using Shimadzu 8400 Co. Ltd., Singapore and the samples were analyzed using Potassium Bromide (KBr) pellets. ¹H-NMR spectra were collected on Bruker Advance II 400 NMR spectrometer using Tetramethyl silane (TMS) as internal standard. The standard abbreviations were used to mark peak multiplicity. Thin Layer Chromatography (TLC) analysis was done to check the purity of the compounds on pre-coated aluminum plates (Silica gel 60 F254 Merck-Germany).

2.1. General procedure:

o-phenylenediamine was dissolved in a mixture of glacial acetic acid and water in a 250ml beaker. Then the clear solution was cooled to 15ºC and magnetically stirred. Then after the aqueous sodium nitrite solution was added to the above solution. Benzotriazole was formed as pale brown solid which was further reacted with ethylchloroacetate and potassium carbonate in acetone to yield ethyl-2-(1H-benzo[1,2,3]triazole-1-yl)acetate and recrystallized from chloroform. Ethyl-2-(1H-benzo[1,2,3]triazole-1-yl) acetate, when reacted with hydrazine hydrate in the presence of ethanol, produced (Benzotriazol-1-yl)acetic acid hydrazide. Finally, the resulted hydrazide produced was condensed with aromatic aldehydes in the presence of ethanol and small amount of glacial acetic acid under microwave conditions to give Schiff ͗ s bases (5a-5f). Synthetic scheme is shown in Fig.3 and list of synthesized derivatives are given in Table 2.

Fig. 3: Scheme for the synthesis of derivatives of Schiff base of benzotriazole

2.2. Characterization of compounds:

Benzotriazole (2):FT-IR (KBr, cm^-¹): 3298 (N-H str), 3066 (C-H str), 1130 (C-N str), 1589 (N=N), 1660 (C=C str), 1485 (C=C str), 1635 (N-H bend), 740 (C=C aromatic)., ¹H-NMR (400MHz, CDCl₃ δ ppm): 7.28-7.99 (m, 4H, benzene); 13.34 (s, 1H, NH).

Ethyl-2-(1H-Benzo[1,2,3]triazole-1-yl)acetate (3):FT-IR (KBr, cm^-¹) : 2985 (C-H str), 2931 (C-H str), 1745 (C=O str), 1213 (C-O str), 1344, (C-N str), 1660 (N=N), 1496 (C=C str), 1475 (C-H, bend, CH₂), 1381 (C-H, bend, CH₃), 1589 (C=C str), 746 (C=C aromatic), ¹H-NMR (400MHz, CDCl₃ δ ppm): 7.28-8.09 (m, 4H, benzene); 5.43 (s, 2H, CH₂); 4.26-4.29 ( m, 2H, CH₂); 1.26-1.31 ( m, 3H, CH₃).

(Benzotriazol-1-yl)acetic acid hydrazide (4):FT-IR (KBr, cm^-¹): 3335 (N-H str), 2922 (C-H, str, alkyl) 3309 (N-H str), 3063 (C-H str), 1649 (C=O str), 1346 (C-N str), 1599 (C=C str), 1494 (C=C str), 1460 (C-H, bend), 1548 (N-H bend), 750 (C=C aromatic), ¹H-NMR (400MHz, CDCl₃ δ ppm): 7.30-7.94 (m, 4H, benzene); 9.6 (s, 1H, NH); 5.29 (s, 2H, CH₂); 2.51 (s,2H, NH₂).

N-(Phenylmethylidene)-2-(1H-benzotriazol-1-yl)acetohydrazide (5a):FT-IR (KBr, cm^-¹): 3091 (N-H str), 3053 (C-H str), 1622 (C=O str), 1315 (C-N str), 2916 (C-H str), 1496 (C=C str), 1681 (C=N str), 1548 (N-H bend), 688 (C=C), 778 (C=C bend), ¹H-NMR (400MHz, DMSO δ ppm): 5.94-8.59 (m, 4H, benzene); 7.81 (s, 1H, CH); 8.81 (s, 1H, NH); 3.70 (s, 2H, CH₂).

N-(2-Chlorophenylmethylidene)-2-(1H-benzotriazol-1-yl)acetohydrazide (5b):FT-IR (KBr, cm^-¹): 3431 (N-H str), 3066 (C-H str), 1681 (C=O str), 2953 (C-H, str, alkyl), 1232 (C-N str), 1589 (C=C str), 559 (C-Cl str), 1460 (C=C str), 1701 (C=N str), 1500 (N-H bend), 750 (C=C bend), ¹H-NMR (400MHz, DMSO δ ppm): 5.98-8.51 (m, 4H, benzene); 7.43 (s, 1H, CH); 8.69 (s, 1H, NH); 3.99 (s, 2H, CH₂).

N-(4-Methoxyphenylmethylidene)-2-(1H-benzotriazol-1-yl)acetohydrazide(5c):FT-IR (KBr, cm^-¹): 3471 (N-H str), 3194 (C-H str), 2920 (C-H, str),1246 (C-O str), 1629 (C=O str), 1600 (C=C str), 1066 (C-O str), 1166 (C-N str), 1585 (N=N), 1454 (C=C str), 1383 (C-H, bend),1548 (N-H bend), 750 (C=C bend), ¹H-NMR (400MHz,DMSO δ ppm): 5.93-8.02 (m, 4H, benzene); 7.62 (s,1H,CH); 8.21 (s,1H,NH); 4.51 (s,2H,CH₂) ; 3.83 (s,3H,CH₃).

N-(3,4-Dimethoxyphenylmethylidene)-2-(1H-benzotriazol-1-yl)acetohydrazide(5d):FT-IR (KBr,cm^-¹): 3443 (N-H str), 3097 (C-H str), 2974 (C-H, str), 1597 (C=O str), 1693 (C=N, str), 1265 (C-O str), 1165 (C-N str), 1128 (C-O, str), 1518 (C=C str), 1396 (C-H, bend), 1581 (N-H bend), 754 (C=C bend) 819 (C=C bend), ¹H-NMR (400MHz,DMSO δ ppm): 5.93-8.04 (m, 4H, benzene) ; 9.85 (s,1H,NH); 4.70 (s,2H,CH₂) ; 3.98 (s,6H,CH₃).

N-(4-Hydroxyphenylmethylidene)-2-(1H-benzotriazol-1-yl)acetohydrazide (5e):FT-IR (KBr, cm^-¹): 3564 (O-H str), 2987 (C-H, str),1232 (C-O str), 1606 (C=O str) 1165 (C-N str), 1585 (C=C str), 1681 (C=N,str), 1452 (C=C str), ¹H-NMR (400MHz,DMSO δ ppm): 5.93-8.03 (m, 4H, benzene) ; 8.1 (s,1H,NH); 4.66 (s,2H,CH₂), 7.87( s,1H,CH),5.49(s,1H,OH).

N-(4-Dimethylaminophenylmethylidene)-2-(1H-benzotriazol-1-yl)acetohydrazide(5f):FT-IR (KBr,cm-1): 3063 (C-H str), 2912 (C-H, str), 1693 (C=N str),1182 (C-N str), 1548 (C=O,str), 1529 (C=C str), 1496 (C=C str), 1367 (C-H,bend), 744 (C=C bend), 815(C=C bend), 1H-NMR (400MHz,DMSO δ ppm): 5.92-8.11 (m, 4H, benzene) ; 9.26 (s,1H,NH); 7.26 (s,1H,CH); 4.66 (s,2H,CH₂) ; 3.04 (s,6H,CH₃)”.

2.3. Antibacterial activity:

The in vitro antibacterial activity of synthesized derivatives was evaluated using Gram-positive and Gram-negative strains (Staphylococcus aureus, Bacillus subtilis and Escherichia coli, Pseudomonas aeruginosa). The activity was performed by cup and plate method[60] at 100μg/mL concentration using Vancomycin as standard for analyzing antibacterial activity of synthesized compounds. The detail is given in Table 3.

3. RESULT AND DISCUSSION:

o-Phenylenediamine was reacted with glacial acetic acid in the presence of sodium nitrite produce benzotriazole. The benzotriazole was further reacted with ethylchloroacetate in dry acetone gave ethyl-2-(1H-benzo[1,2,3]triazole-1-yl)acetate. Then, substituted esters treated with hydrazine hydrate to form (benzotriazol-1-yl) acetohydrazide in the end substituted acetohydrazide were treatment with substituted aldehydes to produce Schiff base of benzotriazole (5a-5f).

Table 2: List of synthesized derivatives and their physiochemical characteristics

Compound Number	R	Molecular Formula	Molecular weight	M. P [°C]	R_f [value]^a	Yield (%)
2	-	C₆H₅N₃	119	99-101	0.75	83.4
3	-	C₁₀H₁₁N₃O₂	205	130-132	0.73	78.2
4	-	C₈H₉N₅O	191	172-174	0.85	80.2
5a	-H	C₁₅H₁₃N₅O	279	185-187	0.83	79.5
5b	2-Cl	C₁₅H₁₂ClN₅O	313	210-212	0.81	82.4
5c	4-OCH₃	C₁₆H₁₅N₅O₂	309	221-223	0.79	81.6
5d	3,4-OCH₃	C₁₇H₁₇N₅O₃	339	265 - 268	0.77	85.2
5e	4-OH	C₁₅H₁₃N₅O₂	295	272 - 274	0.86	80.5
5f	4-N(CH₃)₂	C₁₇H₁₈N₆O	322	290-295	0.80	81.7

^aTLC mobile phase: hexane: Ethyl acetate (7.5:2.5)

Elemental analysis is used to confirm the formula of the synthesized compounds. Structures were confirmed with the help of IR, ¹H NMR and ES-MS spectra. In the IR spectra, all the vibrational bands appeared in the expected regions. A single band of was appeared in the region of 3045-3404 cm^-1 indicate the presence of sec. N-H group. For ester and amide C=O str. Vibrations were appeared at 1735-1749 and 1610-1620 cm^-1. The ¹H NMR spectra used to identify the different types of protons in the synthesized derivatives.

The synthesized Schiff base of benzotriazole showed good antibacterial activity against both Gram positive and Gram-negative bacteria. Compounds 5b,5d and 5e were found to have maximum antibacterial activity as compared to the standard vancomycin.

Table 3. Antibacterial Data of Synthesized Compounds

	Zone of inhibition (mm)
Compound	Gram +ve bacteria		Gram -ve bacteria
	B. subtilis	S. aureus	E. coli	P. aeruginosa
5a	13	20	21	19
5b	23	20	18	17
5c	12	15	14	14
5d	22	19	18	17
5e	19	20	19	18
5f	13	15	14	13
Vancomycin	15	16	18	15
DMSO	0	0	0	0

Fig.4: Antibacterial activity of Schiff’s base of benzotriazole

4. CONCLUSION:

N-substituted benzyliden-2-(1H-benzotriazol-1-yl)acetohydrazide derivatives were synthesized and their chemical structures were interpreted by IR and ¹HNMR techniques. The synthesized derivatives were subjected to in vitro antibacterial activity using B. substilis S. aureus, E. coli and P. aeruginosa by cup-plate method. All the synthesized compounds showed significant activity against the selected bacterial strains. Compounds 5b,5d and 5e were found to have maximum antibacterial activity as compared to the standard vancomycin.

5. ACKNOWLEDGEMENT:

The authors are thankful to Dr. Monica Gulati, Dean, School of Pharmaceutical Sciences, LPU for valuable suggestions, inspiration and providing facilities and authors are also thankful to the second International Conference of Pharmacy, held by the School of Pharmaceutical Sciences, Lovely Professional University on September 13-14, 2019 to fund the publication of this manuscript.

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Received on 19.11.2019 Modified on 29.04.2020

Research J. Pharm. and Tech. 2021; 14(2):823-827.

DOI: 10.5958/0974-360X.2021.00145.1